Transient cholinergic enhancement does not significantly affect either the magnitude or selectivity of perceptual learning of visual texture discrimination.

Perceptual learning (PL), often characterized by improvements in perceptual performance with training that are specific to the stimulus conditions used during training, exemplifies experience-dependent cortical plasticity. An improved understanding of how neuromodulatory systems shape PL promises to provide new insights into the mechanisms of plasticity, and by extension how PL can be generated and applied most efficiently. Previous studies have reported enhanced PL in human subjects following administration of drugs that increase signaling through acetylcholine (ACh) receptors, and physiological evidence indicates that ACh sharpens neuronal selectivity, suggesting that this neuromodulator supports PL and its stimulus specificity. Here we explored the effects of enhancing endogenous cholinergic signaling during PL of a visual texture discrimination task. We found that training on this task in the lower visual field yielded significant behavioral improvement at the trained location. However, a single dose of the cholinesterase inhibitor donepezil, administered before training, did not significantly impact either the magnitude or the location specificity of texture discrimination learning compared with placebo. We discuss potential explanations for discrepant findings in the literature regarding the role of ACh in visual PL, including possible differences in plasticity mechanisms in the dorsal and ventral cortical processing streams.

The role of the hippocampus in object discrimination based on visual features.

The role of rodent hippocampus has been intensively studied in different cognitive tasks. However, its role in discrimination of objects remains controversial due to conflicting findings. We tested whether the number and type of features available for the identification of objects might affect the strategy (hippocampal-independent vs. hippocampal-dependent) that rats adopt to solve object discrimination tasks. We trained rats to discriminate 2D visual objects presented on a computer screen. The objects were defined either by their shape only or by multiple-features (a combination of filling pattern and brightness in addition to the shape). Our data showed that objects displayed as simple geometric shapes are not discriminated by trained rats after their hippocampi had been bilaterally inactivated by the GABAA-agonist muscimol. On the other hand, objects containing a specific combination of non-geometric features in addition to the shape are discriminated even without the hippocampus. Our results suggest that the involvement of the hippocampus in visual object discrimination depends on the abundance of object's features.

N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.

RATIONALE: Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits. OBJECTIVES: The objective of this study is to investigate N-acetyl cysteine (NAC) as a therapeutic antioxidant to reverse schizophrenia-like bio-behavioural changes in rats exposed to maternal immune activation (MIA), adolescent methamphetamine (MA) or a combination thereof. METHODS: Sprague-Dawley offspring prenatally exposed to saline/lipopolysaccharide (LPS) received saline or MA (0.2-6 mg kg-1 twice daily × 16 days) during adolescence and divided into LPS, MA and LPS + MA groups. Vehicle/NAC (150 mg kg-1 × 14 days) was administered following MA/saline exposure on postnatal day 51-64. Social interaction, novel object recognition and prepulse inhibition (PPI) of startle, as well as regional brain monoamines, lipid peroxidation, plasma reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines (TNF-α; IL-10), were assessed. RESULTS: NAC reversed LPS, MA and LPS + MA-induced anxiety-like social withdrawal behaviours, as well as MA and LPS + MA-induced deficits in recognition memory. PPI deficits were evident in MA, LPS and LPS + MA models, with NAC reversing that following LPS + MA. NAC reversed LPS, MA and LPS + MA-induced frontal cortical dopamine (DA) and noradrenaline (NA) elevations, LPS and LPS + MA-induced frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and striatal NA deficits as well as LPS + MA-induced frontal cortical 5-HT turnover. Decreased IL-10 in the LPS, MA and LPS + MA animals, and increased TNF-α in the LPS and MA animals, was reversed with NAC. NAC also reversed elevated lipid peroxidation and ROS in the LPS and LPS + MA animals. CONCLUSIONS: Prenatal LPS, LPS + postnatal MA challenge during adolescence, and to a lesser extent MA alone, promotes schizophrenia-like bio-behavioural changes later in life that are reversed by NAC, emphasizing therapeutic potential for schizophrenia and MA-associated psychosis. The nature and timing of the dual-hit are critical.

Effects of nicotine on response inhibition and interference control.

Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7 mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N = 44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial.

PURPOSE: Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. METHODS: Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. RESULTS: Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to <0.0001). CONCLUSIONS: Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity. From the relationship between RBC-DHA and the rate of field sensitivity loss, we can extrapolate that an RBC-DHA level of 17% could minimize the decline in field sensitivity. (ClinicalTrials.gov number, NCT00100230.)

GABAB receptor antagonist CGP46381 inhibits form-deprivation myopia development in guinea pigs.

The aim was to investigate the effects of the GABAB receptor antagonist, CGP46381, on form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25). The deprived eyes were treated with daily subconjunctival injections (100 µl) of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD) and axial length (AL) using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes, P < 0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA, P < 0.0001). The highest dose tested, 2% CGP46381, significantly inhibited myopia development compared to saline (2% CGP46381: -1.08 ± 0.40 D, saline: -4.33 ± 0.67 D, P < 0.01). The majority of these effects were due to less AL (2% CGP46381: 0.03 ± 0.01 mm, saline: 0.13 ± 0.02 mm, P < 0.01) and VCD (2% CGP46381: 0.02 ± 0.01 mm, saline: 0.08 ± 0.01 mm, P < 0.01) elongation. The lower dose tested, 0.2% CGP46381, did not significantly inhibit FDM (P > 0.05). Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.

Wnt signaling in form deprivation myopia of the mice retina.

BACKGROUND: The canonical Wnt signaling pathway plays important roles in cellular proliferation and differentiation, axonal outgrowth, cellular maintenance in retinas. Here we test the hypothesis that elements of the Wnt signaling pathway are involved in the regulation of eye growth and prevention of myopia, in the mouse form-deprivation myopia model. METHODOLOGY/PRINCIPAL FINDINGS: (1) One hundred twenty-five C57BL/6 mice were randomly distributed into form-deprivation myopia and control groups. Form-deprivation myopia (FDM) was induced by suturing the right eyelid, while the control group received no treatment. After 1, 2, and 4 weeks of treatment, eyes were assessed in vivo by cycloplegic retinoscopic refraction and axial length measurement by photography or A-scan ultrasonography. Levels of retinal Wnt2b, Fzd5 and ß-catenin mRNA and protein were evaluated using RT-PCR and western blotting, respectively. (2) Another 96 mice were divided into three groups: control, drugs-only, and drugs+FDM (by diffuser). Experimentally treated eyes in the last two groups received intravitreal injections of vehicle or the proteins, DKK-1 (Wnt-pathway antagonist) or Norrin (Wnt-pathway agonist), once every three days, for 4 injections total. Axial length and retinoscopic refraction were measured on the 14th day of form deprivation. Following form-deprivation for 1, 2, and 4 weeks, FDM eyes had a relatively myopic refractive error, compared with contralateral eyes. There were no significant differences in refractive error between right and left eye in control group. The amounts of Wnt2b, Fzd5 and ß-catenin mRNA and protein were significantly greater in form-deprived myopia eyes than in control eyes.DKK-1 (antagonist) reduced the myopic shift in refractive error and increase in axial elongation, whereas Norrin had the opposite effect in FDM eyes. CONCLUSIONS/SIGNIFICANCE: Our studies provide the first evidence that the Wnt2b signaling pathway may play a role in the development and progression of form-deprivation myopia, in a mammalian model.

Amyloid beta 25-35 impairs reconsolidation of object recognition memory in rats and this effect is prevented by lithium carbonate.

Previous studies in transgenic mice models of Alzheimer's disease (AD) have demonstrated an age dependent memory reconsolidation failure, suggesting that this may be an additional mechanism that contributes to the memory impairment observed in AD. However, so far it is unknown whether this effect can be caused by exogenous administration of amyloid beta (Aß). The purpose was to determine the effects of soluble Aß 25-35 on reconsolidation of object recognition memory (ORM) in rats, and assess whether these effects can be prevented by lithium carbonate (LiCa). In this study, male Wistar rats were used and the following groups were formed (N=6-13): (a) control, given saline solution; (b) [NMDA antagonist] MK-801 (0.1 mg/kg); (c) LiCa (350 mg/kg); (d) Aß 25-35 (100 µM) injected into both hippocampi; and (e) Aß 25-35+LiCa. In all cases, treatments were administered with or without reactivation of memory. The results showed that soluble Aß 25-35 produces ORM impairment similar to MK-801 when given shortly after memory reactivation, and this effect is prevented by prior administration of LiCa.

Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors.

17ß-estradiol (E2), at high circulating levels, enhances learning and memory in many women, making it a clinical treatment for hormone-related cognitive decline in aging. However, the mechanisms stimulated by E2, which are responsible for its cognitive enhancing effects, remain incompletely defined. Using an ovariectomized rat model, we previously reported that increasing plasma E2 enhances the magnitude of long-term potentiation (LTP) at hippocampal CA3-CA1 synapses, which is caused by a selective increase in current mediated by NR2B-containing NMDARs, leading to an increase in the NMDAR/AMPAR ratio. Whether the increase in NR2B current is causally related to the ability of E2 to enhance hippocampal dependent learning and memory has yet to be tested. Here, we find that E2 enhances performance in the novel object recognition (NOR) task with the same time course we previously showed E2 enhances the LTP magnitude, temporally linking the increase in LTP to enhanced learning and memory. Furthermore, using the selective NR2B subunit antagonist Ro25-6981, we find that the E2-enhanced NOR, like the enhanced LTP, requires hippocampal NR2B-containing NMDARs, specifically in area CA1. Finally, using whole-cell recordings and the phosphatase inhibitor orthovanadate, we investigated whether the E2-induced increase in NMDAR current is caused by an increase in the density of synaptic NMDARs and/or an increase in NMDAR subunit phosphorylation. We find that both mechanisms are responsible for the enhanced NMDAR current in E2-treated rats. Our results show that the E2-enhanced NOR requires a functional increase in NR2B-containing NMDARs, a requirement shared with the E2-enhanced LTP magnitude at CA3-CA1 synapses, supporting the hypothesis that the increase in LTP likely contributes to the enhanced learning and memory following an increase in plasma E2 levels.

Effects of ethanol, Δ(9)-tetrahydrocannabinol, or their combination on object recognition memory and object preference in adolescent and adult male rats.

Recent advances have been made in our understanding of the deleterious effects of both ethanol and THC on adolescent behavior and brain development. However, very little is known about the combined effects of EtOH+THC during adolescence, a time in which these drugs are often used together. The purpose of this experiment was to: (1) determine whether EtOH and/or THC induced greater working memory impairment in adolescent than adult male rats using the novel object recognition (NOR) task and (2) determine whether the EtOH+THC combination would produce a more potent additive effect in adolescents than adults when compared to these drugs alone. NOR was performed with a 24h delay under each of the four drug conditions: vehicle; 1.5g/kg ethanol; 1.0mg/kg THC; and 1.5g/kg EtOH+1.0mg/kg THC, at 72h intervals. The results show that there was an age effect on working memory in NOR after the EtOH+THC challenge. Specifically, adolescent animals showed a preference for the familiar object whereas adults showed no preference for the novel or familiar object, the latter being characteristic of a classic working memory deficit. These effects were not dependent on changes in exploration across session, global activity across drug condition, or total object exploration. These novel findings clearly indicate that further understanding of this age-drug interaction is crucial to elucidating the influence that adolescent EtOH+THC use may have on repeated drug use and abuse later in life.

Does alcohol consumption really affect asymmetry perception? A three-armed placebo-controlled experimental study.

AIMS: A possible explanation for increased levels of attractiveness of faces when under the influence of alcohol is the reduced ability to perceive bilateral asymmetry. This study tested the degree of preference by alcohol-dosed and non-alcohol-dosed participants for symmetrical faces and their ability to detect facial symmetry, while controlling for other explanations. DESIGN: Volunteers were recruited to a random allocation experiment with three conditions: alcoholic drink (alcohol dosed), non-alcoholic drink (placebo) and diluted orange cordial (control). Data on concentration, personality and demographics were collected. Dependent variables were symmetry preference and detection. SETTING: Laboratory, University of Roehampton. PARTICIPANTS: A total of 101 participants, mainly students (41 alcohol-dosed, 40 placebo, 20 control). MEASUREMENTS: Participants provided verbal responses to images of faces which were presented on a computer screen for 5 seconds each; the first task required a preference judgement and the second task consisted of a forced-choice response of whether or not a face was symmetrical. Levels of concentration, weight and level of alcohol dose were measured, and demographics plus additional psychological and health information were collected using a computer-based questionnaire. FINDINGS: In contrast to a previous investigation, there was no difference in symmetry preference between conditions (P = 0.846). In agreement with previous findings, participants who had not drunk alcohol were better at detecting whether a face was symmetrical or asymmetrical (P = 0.043). Measures of concentration did not differ between conditions (P = 0.214-0.438). Gender did not affect ability to detect symmetry in placebo or alcohol-dosed participants (P = 0.984, 0.499); however, alcohol-dosed females were shown to demonstrate greater symmetry preference than alcohol-dosed males (P = 0.004). CONCLUSIONS: People who are alcohol-dosed are subtly less able to perceive vertical, bilateral asymmetry in faces, with gender being a possible moderating factor.

The effect of betel nut chewing on contour and object masking.

The betel nut is a common stimulant in many Asian countries. We employed the masking task developed by Enns and Di Lollo (Trends in Cognitive Sciences, 4, 345-352, 1997) to investigate the effects of betel nuts on sensory and attentional processing. In the masking task, participants needed to identify a target that was masked by either a contour mask or an object mask. Sensory processing was assessed by examining target identification in the contour mask condition when the target was presented only centrally, whereas attentional processing was assessed by examining target identification in the object mask condition when the target was presented randomly in either a central or a parafoveal location. The results showed that chewing betel nut and chewing gum produced significant contour masking with a large effect size, similar to the pure control condition, in which participants chewed nothing, and the placebo control condition, in which what participants chewed was disguised. This suggests that neither betel nut nor gum affects sensory processing. Alternatively, betel nut chewing could produce a reduction in object masking for the habitual chewers and the nonchewers, suggesting an effect of betel nut on attentional processing. This concentrated attention was also observed in the placebo control condition; thus, it cannot be exclusively driven by the expectation effect. Also, chewing per se reduced the attentional distribution foveally.

Perception of simulated local shapes using active and passive touch.

This study reexamined the perceptual equivalence of active and passive touch using a computer-controlled force-feedback device. Nine subjects explored a 6 x 10-cm workspace, with the index finger resting on a mobile flat plate, and experienced simulated Gaussian ridges and troughs (width, 15 mm; amplitude, 0.5 to 4.5 mm). The device simulated shapes by modulating either lateral resistance with no vertical movement or by vertical movement with no lateral forces, as a function of the digit position in the horizontal workspace. The force profiles and displacements recorded during active touch were played back to the stationary finger in the passive condition, ensuring that stimulation conditions were identical. For the passive condition, shapes simulated by vertical displacements of the finger had lower categorization thresholds and higher magnitude estimates compared with those of active touch. In contrast, the results with the lateral force fields showed that with passive touch, subjects recognized that a stimulus was present but were unable to correctly categorize its shape as convex or concave. This result suggests that feedback from the motor command can play an important role in processing sensory inputs during tactile exploration. Finally, subjects were administered a ring-block anesthesia of the digital nerves of the index finger and subsequently retested. Removing skin sensation significantly increased the categorization threshold for the perception of shapes generated by lateral force fields, but not for those generated by displacement fields.

Occupational styrene exposure and neurobehavioural functions: a cohort study with repeated measurements.

OBJECTIVE: Associations between occupational styrene exposure and cognitive as well as psychomotor functions were investigated with a view to answering three questions: (1) are the published results for neurobehavioural impairment reproducible, (2) if such effects exist, are they related to current or to chronic exposure and (3) if effects exist, are there reductions in the effects during an exposure-free period. METHODS: Workers from a boat-building plant, some of whom were laminators, were investigated in groups of low (n = 83, mean mandelic acid MA + phenylglyoxylic acid PGA = 53 mg/g creatinine), medium (n = 101, 230 mg/g creat.) and high (n = 29, 928 mg/g creat.) levels of exposure to styrene. The mean job tenure was about 6 years. In addition, subgroups chronically exposed to low-short (n = 30, lifetime weighted average exposure mean 184 mg/g creat. for 6 years) and high-long (n = 16, 693 mg/g creat., 15 years) styrene levels were analyzed. The examinations were carried out during normal working days and during the company holidays. A symptom questionnaire and the tests Benton visual retention, symbol digit substitution and digit span for cognitive functions as well as choice reaction, aiming, peg board, tapping, and steadiness for psychomotor functions were administered. Co-variance analyzes with repeated measurements and linear regressions were used for statistical analysis. Co-factors were education, age, job tenure, long-term alcohol consumption, and German as mother tongue. In some cases also the activity as a laminator was considered. RESULTS: Symptoms were not related to exposure. The tests for cognitive functions generally revealed (all variance analyses) no exposure-related associations. Only the linear regressions of Benton test results showed significant correlation with parameters of chronic exposure which was still evident as a tendency in the work-free and exposure-free period. Most tests for psychomotor functions also revealed no relationships with exposure. However, the peg board test results showed significant correlations with chronic exposure which disappeared during holidays. The activity as a laminator--considered in addition to exposure parameters--was significant as a factor to explain the variability of psychomotor variables. CONCLUSION: Acute exposures to up to 40 ppm styrene and long-term exposures to about 27 ppm averaged over a period of 15 years were not identified as being associated with an elevated risk of developing impaired cognitive and psychomotor functions or increased symptom levels with the tests applied. This statement must be qualified by two exceptions: performances in the Benton test and in a finger dexterity test were associated with parameters of long-term exposure as a dose-response relationship, but not with current exposure.

Dopamine D4 receptor antagonist L745,870 abolishes cognitive effects of intracerebroventricular angiotensin IV and des-Phe(6)-Ang IV in rats.

In this study effect of L745,870, a selective D(4) dopamine (DA) receptor blocker, on the pro-cognitive action of intracerebroventricularly (icv) injected angiotensin IV (Ang IV) and des-Phe(6)-Ang IV was examined. Male Wistar rats weighing 180-200 g were used. Both peptides given at the dose of 1 nmol facilitated recall of a passive avoidance (PA) behaviour, improved object recognition (OR) memory, decreased number of errors, increased number of sequential correct entries and shortened time-to-goal in an eight-arm radial maze (RM). In the auxiliary tests performed to control for the participation of unspecific motor (open field, OF) and emotional ('plus' maze, PM) effects of our treatment in the results of memory tests they had either no (OF) or negligible (PM) effects. Intraperitoneal pretreatment of the animals with 1 mg/kg of L745,870 abolished effects of both peptides on PA and OR and slightly diminished those observed in the eight-arm RM.

Evaluation of a new method of assessing depth of sedation using two-choice visual reaction time testing on a mobile phone.

The utility of two-choice visual reaction time testing using a specially programmed mobile telephone as a measure of sedation level was investigated in 20 healthy patients sedated with target controlled infusions of propofol. At gradually increasing target concentrations visual reaction time was compared with patient-assessed visual analogue scale sedation scores and an observer-rated scale. Propofol sedation caused dose-dependent increases in visual reaction time and visual analogue scale scores that were statistically significant when the calculated effect-site concentration reached 0.9 microg.ml(-1) (p < 0.05) and 0.5 microg.ml(-1) (p < 0.01) respectively. While visual analogue scale scores were more sensitive at lower levels of sedation than visual reaction time, the latter demonstrated marked increase in values at higher levels of sedation. Visual reaction time may be useful for identifying impending over-sedation.

Recognition of category-related visual stimuli in Parkinson's disease: before and after pharmacological treatment.

Visual-sensory dysfunctions and semantic processing impairments are widely reported in Parkinson's disease (PD) research. The present study investigated the category-specific deficit in object recognition as a function of both the semantic category and spatial frequency content of stimuli. In the first experiment, the role of dopamine in object-recognition processing was assessed by comparing PD drug naïve (PD-DN), PD receiving levodopa treatment (PD-LD), and control subjects. Experiment 2 consisted of a retest session for PD drug naïve subjects after a period of pharmacological treatment. All participants completed an identification task which displayed animals and tools at nine levels of filtering. Each object was revealed in a sequence of frames whereby the object was presented at increasingly less-filtered images up to a complete version of the image. Results indicate an impaired identification pattern for PD-DN subjects solely for animal category stimuli. This differential pharmacological therapy effect was also confirmed at retest (experiment 2). Thus, our data suggest that dopaminergic loss has a specific role in category-specific impairment. Two possible hypotheses are discussed that may account for the defective recognition of semantically different objects in PD.

Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects.

Methylphenidate (MPD) is widely prescribed for the treatment of attention deficit disorders in children and has generally been thought to be free of significant side effects when administered at recommended therapeutic doses. However, recent behavioral research with laboratory rodents has indicated that, like other psychostimulants with which it shares neurotransmitter-modulating properties, chronically administered MPD can bring about lasting and potentially detrimental alterations in brain function. Some of these may involve changes in the neuromodulatory input from noradrenergic and dopaminergic systems that project to the prefrontal cortex and hippocampus, regions with significant roles in several cognitive functions, including those critical to memory formation. To investigate the possibility of cognitive impairment, the effects of a regimen of chronic MPD on the performance of an object recognition task known to rely on the integrity of systems involved in rodent memory was assessed. The drug, at doses of 2, 3 or 5mg/kg, was delivered twice daily to periadolescent rats via an oral administration technique on either 11 or 21 treatment days. Subsequent to this period, the animals were subjected to an object recognition test at 14, 28, and 42 days after their last MPD treatment. In each of these tests, exploration time for two objects, one novel and one previously encountered (3h earlier), was assessed. Longer exploration of the novel object was considered evidence of retained memory for the familiar object. It was found that rats exposed to 3 or 5mg/kg (b.i.d.) on 21 occasions exhibited no significant preference for exploration of the novel object at any of the three post-treatment intervals. This finding was interpreted as evidence of a persisting MPD-induced impairment of recognition memory in these animals.

NMDA receptor modulation by D-cycloserine promotes episodic-like memory in mice.

RATIONALE: NMDA-R (N-methyl-D-aspartate receptors) have been implicated in synaptic plasticity underlying one-trial learning of event-place associations. In rodents, episodic-like memory (ELM) of personally experienced events can be inferred from behavior that reflects the remembrance of the content (what kind of object was presented), place (where was this object placed), and temporal context (when was the object presented). We have previously shown that that D-cycloserine (DCS), an NMDA-R agonist, ameliorates stress-induced deficits in ELM. OBJECTIVES: In this study, we used an experimental protocol designed to detect promnestic drug effects and investigated whether DCS, which is known to enhance learning and memory, can induce ELM under conditions where mice normally do not show ELM. RESULTS: Mice that have been treated i.p. with DCS (20 mg/kg) both remembered the temporal order in which two different objects had been encountered during two consecutive sample trials, as well as their spatial position during the sample trials. Most importantly, the test trial performance of these mice is compatible with ELM in terms of an integrated memory for unique experiences comprising "what", "where", and "when" information. In contrast, mice that have received either a saline injection or lower doses of DCS (0.2 and 2.0 mg/kg) did not show such an integrated ELM. CONCLUSIONS: To our knowledge, this is the first report showing that DCS can promote ELM in mice.

The effect of chronic peripubertal cannabinoid treatment on deficient object recognition memory in rats after neonatal mPFC lesion.

We here report on behavioral effects of neonatal medial prefrontal cortex (mpfc) lesions in rats, followed by chronic peripubertal treatment with the cannabinoid full agonist WIN 55,212-2 (WIN). Rat pups received excitotoxic lesions of the mpfc on postnatal day (pd) 7. Chronic WIN (1.2 mg/kg) treatment was extended throughout the rats' puberty (pd 40-65). All animals were tested as juveniles and adults for short-term memory functioning using the spontaneous object recognition test, and for locomotor activity in an open field. Lesioned rats showed impairments in recognition memory when tested prepubertally. Postpubertal testing of lesioned animals revealed a persisting recognition memory impairment that was intensified by pubertal WIN treatment. Chronic WIN treatment during puberty also affected recognition memory in sham-lesioned rats and controls. No effects on locomotor activity of either neonatal lesion or pubertal cannabinoid treatment were found. This study shows that behavioral deviations induced by neonatal mPFC lesions can be exacerbated by pubertal chronic cannabinoid treatment, leading to long-lasting impairments of mnemonic short-term information processing.